Process for preparing substituted benzimidazole compounds

ABSTRACT

The invention relates to new methods of preparing substituted benzimidazole compounds, such as 2-bromo-5,6-dichlorobenzimidazole, which are useful in the preparation of compounds having antiviral activity.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to new processes for thepreparation of substituted benzimidazole compounds.

[0002] Certain substituted benzimidazole nucleosides have been shown topossess antiviral activity. PCT Publication No. WO 98/56761 teaches aseries of substituted benzimidazole pyranosyls having antiviralactivity, and processes for preparing the same. PCT Publication Nos. WO92/07867, 96/01833, 97/25337, 99/06424 teach a series of substitutedbenzimidazole furanosyls, including substituted benzimidazole furanosylshaving antiviral activity, and processes for preparing the same.

[0003] U.S. Pat. No. 5,003,079 is directed toward a process for thepreparation of benzimidazolones. E. Kawashima, et al. HeterocyclicCompounds 4:2426 (1991), relates to a process for preparing2,5,6-trichlorobenzimidazole. L. Townsend, J. Med. Chem. 38:4098 (1995),relates to a process for synthesizing certain2,5,6-trihalo-1-(β-D-ribofuranosyl)benzimidazoles.

SUMMARY OF THE INVENTION

[0004] Generally, the present invention provides new processes for thesynthesis of substituted benzimidazole compounds.

[0005] As a first aspect, the present invention provides a process forpreparing a compound of formula I:

[0006] wherein X is halo. The process comprises the steps of: (a)cyclizing 4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole toyield a compound of formula II:

[0007] and

[0008] (b) reacting the compound of formula II with PO(X)₃ to prepare acompound of formula I.

[0009] In a further aspect, the present invention provides a process forpreparing 2-bromo-5,6-dichlorobenzimidazole which comprises reacting a5,6-dichlorobenzimidazole-2-one with phosphorous oxybromide.

[0010] In a further aspect of the invention, there is provided a processfor preparing a compound of formula VI:

[0011] wherein R is halo; R¹ is hydrogen; each of R², R³, R⁴, R⁵, R⁶ andR⁷ is independently selected from the group consisting of H, hydroxy andprotected hydroxy group; and pharmaceutically acceptable derivatives andprodrugs thereof. The process comprising the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

[0012] (b) reacting the compound of formula II with PO(X)₃ wherein X ishalo, to prepare a compound of formula I:

[0013] (c) reacting the compound of formula I with a pyranoside offormula IV:

[0014] to prepare a compound of formula VI and pharmaceuticallyacceptable derivatives and prodrugs thereof.

[0015] In a further aspect of the invention, there is provided a processfor preparing 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazoleand pharmaceutically acceptable derivatives and prodrugs thereof. Theprocess comprising: (a) reacting 5,6-dichlorobenzimidazol-2-one withphosphorous oxybromide to produce 2-bromo-5,6-dichlorobenzimidazole; (b)reacting 2-bromo-5,6-dichlorobenzimidazole with1,2,3,4-tetra-O-acetyl-p-D-ribopyranose to produce2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazole;and (c) deprotecting2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazoleto produce 2-bromo-5,6-dichloro-1-p-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof. Thus, thepresent invention provides a process for preparing2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazoleby performing steps (a) and (b) above, without also carrying out step(c) of deprotecting (or removing the O-acetyl protecting groups). Theprocess may further comprise the preliminary step of preparing5,6-dichlorobenzimidazol-2-one by cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole.

[0016] In yet another aspect, the present invention provides a processfor preparing compounds of formula VII:

[0017] wherein:

[0018] R is —NR⁸R⁹ where R⁸ and R⁹ are each independently selected fromthe group consisting of H, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl, andCOC₁₋₆alkyl;

[0019] each R¹⁰ is independently selected from the group consisting ofhydroxy and protected hydroxy group; and pharmaceutically acceptablederivatives and prodrugs thereof.

[0020] The process comprises the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

[0021] (b) reacting the compound of formula II with PO(X)₃ wherein X ishalo, to prepare a compound of formula I:

[0022] (c) reacting the compound of formula I with a furanosyl offormula III:

[0023] to prepare a compound of formula V:

[0024] (d) reacting the compound of formula V with an amine of formulaH—NR⁸R⁹; to prepare a compound of formula VII and pharmaceuticallyacceptable derivatives and prodrugs thereof.

[0025] In yet another aspect, the present invention provides a processfor preparing compounds of formula X:

[0026] wherein:

[0027] R is selected from the group consisting of halo, hydroxy, azido,C₁₋₈alkyl, trihalomethyl, C₁₋₈alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₄arylC₂₋₆alkenyl, C₆₋₁₄arylC₂₋₆alkynyl,

[0028] —NR²⁵R²⁶ wherein R²⁵ and R²⁶ may be the same or different and areeach independently selected from the group consisting of H, halo,C₁₋₈alkyl, cyanoC₁₋₈alkyl, hydroxyC₁₋₈alkyl, haloC₁₋₈alkyl,C₃₋₇cycloalkyl, C₁₋₈alkyl-C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₃₋₇cycloalkylC₁₋₈alkyl, C₂₋₆alkynyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₆alkyl,heterocyclylC₁₋₈alkyl, C₁₋₈alkylcarbonyl, and C₆₋₁₄aryl-sulfonyl;

[0029] —NHNR³⁰R³¹ wherein R³⁰ and R³¹ are the same or different and areeach independently C₁₋₆alkyl;

[0030] —N═NNC₁₋₆alkyl;

[0031] —NHOC₁₋₆alkyl;

[0032] —OR²⁷ wherein R²⁷ is selected from the group consisting ofC₁₋₈alkyl, C₃₋₇cycloalkyl, and C₆₋₁₄aryl;

[0033] —SR²⁸ wherein R²⁸ is selected from the group consisting of H,C₁₋₈alkyl, hydroxyC₁₋₈alkyl, C₃₋₇cycloalkyl, C₆₋₁₄aryl, andC₆₋₁₄arylC₁₋₆alkyl;

[0034] R¹⁵ is selected from the group consisting of H, halo, C₁₋₆alkylor C₂₋₆alkenyl;

[0035] R¹⁶ and R¹⁷ may be the same or different and are eachindependently selected from the group consisting of H, halo, C₁₋₈alkyl,C₆₋₁₄aryl, heterocyclylC₁₋₈aryl, C₁₋₈ alkoxy, haloC₁₋₈alkyl, NO₂, andSR²⁹ where R²⁹ is selected from the group consisting of H, C₁₋₈alkyl,C₆₋₁₄aryl or C₆₋₁₄arylC₁₋₈alkyl; and

[0036] R²⁰ is a D- or L-sugar moiety selected from the group consistingof:

[0037] wherein

[0038] R²¹ and R²² may be the same or different and are eachindependently selected from the group consisting of H, hydroxy,protected hydroxy group, halo, C₁₋₈alkyl, C₁₋₈ alkylhydroxy,haloC₁₋₈alkyl, or C₁₋₈alkoxy;

[0039] R²³ is selected from the group consisting of H, hydroxy,protected hydroxy group, C₁₋₈ alkyl, C₁₋₈alkoxy, CH₂R³² wherein R³² ishydroxy, protected hydroxy group, halo, or azido; and C(R³³)₃ whereineach R³³ is halo;

[0040] and wherein R²¹, R²² and R²³ may be in the α- or β-position;

[0041] and pharmaceutically acceptable derivatives and prodrugs thereof.The process comprises the steps of:

[0042] (a) cyclizing a phenylenediamine of formula XI:

[0043] with carbonyl di-imidazole to yield a compound of formula XII:

[0044] (b) reacting the compound of formula XII with PO(X)₃, wherein Xis halo, to prepare a compound of formula XIII:

[0045] (c) reacting the compound of formula XIII with a 5- or6-membered, D- or L-sugar selected from the group consisting of:

[0046] wherein

[0047] L is a leaving group in the α- or β-position to prepare compoundsof formula X:

[0048] wherein R¹⁵, R¹⁶, R¹⁷, and R²⁰ are as defined above and R ishalo, and

[0049] pharmaceutically acceptable derivatives and prodrugs thereof; and

[0050] (d) optionally converting the compound of formula X orpharmaceutically acceptable derivative or prodrug thereof into a furthercompound of formula X or pharmaceutically acceptable derivative orprodrug thereof by nucleophilic substitution.

DETAILED DESCRIPTION OF THE INVENTION

[0051] The term “alkyl”, alone or in combination with any other term,refers to a straight-chain or branch-chain saturated aliphatichydrocarbon radical containing the specified number of carbon atoms, orwhere no number is specified, preferably from 1-10 and more preferablyfrom 1-6 carbon atoms. Examples of alkyl radicals include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like, withmethyl and ethyl being preferred.

[0052] The term “alkenyl,” alone or in combination with any other term,refers to a straight-chain or branched-chain mono- or poly-unsaturatedaliphatic hydrocarbon radical containing the specified number of carbonatoms, or where no number is specified, preferably from 2-10 carbonatoms and more preferably, from 2-6 carbon atoms. References to alkenylgroups include groups which may be in the E- or Z-form or a mixturethereof and which when they contain at least three carbon atoms, may bebranched. Examples of alkenyl radicals include, but are not limited to,ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- andZ-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z, E- andZ,Z-hexadienyl and the like.

[0053] The term “alkynyl” refers to hydrocarbon groups of either astraight or branched configuration with one or more carbon-carbon triplebonds which may occur in any stable point along the chain, such asethynyl, propynyl, butynyl, pentynyl, and the like.

[0054] The term “alkoxy” refers to an alkyl ether radical, wherein theterm “alkyl” is defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, with methoxybeing preferred.

[0055] Alkenyl and alkynyl substituents may optionally contain one ormore heteroatoms such as nitrogen, sulfur, or oxygen.

[0056] The term “aryl,” alone or in combination with any other term,refers to a carbocyclic aromatic radical (such as phenyl or naphthyl)containing the specified number of carbon atoms, preferably from 6-14carbon atoms, and more preferably from 6-10 carbon atoms, optionallysubstituted with one or more substituents selected from C1-6 alkoxy,(for example methoxy), nitro, halogen, (for example chloro), amino,carboxylate and hydroxy. Examples of aryl radicals include, but are notlimited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl,anthracenyl and the like.

[0057] The term “heterocycle” and “heterocyclic” radical, unlessotherwise defined herein, refers to a stable 3-7 membered monocyclicheterocyclic ring or 8-11 membered bicyclic heterocyclic ring which iseither saturated or unsaturated, and which may be optionally benzofusedif monocyclic. Each heterocycle consists of one or more carbon atoms andfrom one to four heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. As used herein, the terms “nitrogen andsulfur heteroatoms” include any oxidized form of nitrogen and sulfur,and the quaternized form of any basic nitrogen. A heterocyclyl radicalmay be attached at any endocyclic carbon or heteroatom which results inthe creation of a stable structure. Preferred heterocycles include 5-7membered monocyclic heterocycles and 8-10 membered bicyclicheterocycles. Examples of such groups include imidazolyl, imidazolinoyl,imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl,perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl,pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl,thiomorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl,tetrazolyl, thiazolidinyl, benzofuranoyl, thiomorpholinyl sulfone,oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl,azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl,tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl,oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl,sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl,tetrahydropyranodihydrofuranyl, dihydropyranyl, tetrahydrofurofuranyland tetrahydropyranofuranyl.

[0058] Preferred heterocycles include imidazolyl, pyrrolyl, pyrrolinyl,piperidinyl, piperazinyl, and morpholinyl.

[0059] The terms “halo” or “halogen” refers to a radical of fluorine,chlorine, bromine or iodine.

[0060] The term “haloC₁₋₈ alkyl” means a C₁₋₈alkyl group in which one ormore hydrogens is replaced by halo and preferably containing one, two orthree halo groups. Examples of such groups include trifluoromethyl andfluoroisopropyl.

[0061] As used herein, the compounds synthesized according to thepresent invention are defined to include pharmaceutically acceptablederivatives or prodrugs thereof. A “pharmaceutically acceptablederivative” or “pharmaceutically acceptable prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound described herein which, upon administration toa recipient, is capable of providing (directly or indirectly) a compounddescribed herein or an inhibitorily active metabolite or residuethereof. Particularly favored derivatives and prodrugs are those thatincrease the bioavailability of the compounds described herein when suchcompounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0062] The compounds described herein may be used in the form of saltsderived from inorganic or organic acids. Included among such acid salts,for example, are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleatemethanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectianate, persulfate, phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0063] Pharmaceutically acceptable salts of the compounds describedherein include those derived from pharmaceutically acceptable inorganicand organic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicyclic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic andbenzenesulfonic acids. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsdescribed herein and their pharmaceutically acceptable acid additionsalts.

[0064] Salts derived from appropriate bases include alkali metal (e.g.sodium), alkaline earth metal (e.g., magnesium), ammonium and N-W+4(wherein W is C₁₋₄ alkyl). Physiologically acceptable salts of ahydrogen atom or an amino group include salts or organic carboxylicacids such as acetic, lactic, tartaric, malic, isethionic, lactobionicand succinic acids; organic sulfonic acids such as methanesulfonic,ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids andinorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamicacids. Physiologically acceptable salts of a compound with a hydroxygroup include the anion of said compound in combination with a suitablecation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄alkyl group).

[0065] Pharmaceutically acceptable salts include salts of organiccarboxylic acids such as ascorbic, acetic, citric, lactic, tartaric,malic, maleic, isothionic, lactobionic, p-aminobenzoic and succinicacids; organic sulfonic acids such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids and inorganic acids such ashydrochloric, sulfuric, phosphoric, sulfamic and pyrophosphoric acids.

[0066] Preferred salts include salts formed from hydrochloric, sulfuric,acetic, succinic, citric and ascorbic acids.

[0067] Preferred esters of the compounds described herein areindependently selected from the following groups: (1) carboxylic acidesters obtained by esterification of the hydroxy groups, in which thenon-carbonyl moiety of the carboxylic acid portion of the ester groupingis selected from straight or branched chain alkyl (for example, acetyl,n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example,methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (forexample, phenoxymethyl), aryl (for example, phenyl optionallysubstituted by, for example, halogen, C₁₋₄alkyl, or C₁₋₄alkoxy oramino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (forexample, methanesulfonyl); (3) amino acid esters (for example, L-valylor L-isoleucyl); (4) phosphonate esters and (5) mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di (C₆₋₂₄)acyl glycerol.

[0068] In such esters, unless otherwise specified, any alkyl moietypresent advantageously contains from 1 to 18 carbon atoms, particularlyfrom 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms,Any cycloalkyl moiety present in such esters advantageously containsfrom 3 to 6 carbon atoms. Any aryl moiety present in such estersadvantageously comprises a phenyl group.

[0069] Preferred carboxylic acid esters of compounds according to theinvention include the acetate, butyrate and valerate esters. L-valyl isa particularly preferred amino acid ester.

[0070] Any reference herein to any of the compounds which can besynthesized by the processes of the present invention also includes areference to a pharmaceutically acceptable derivatives and prodrugsthereof.

[0071] The compounds of formula I:

[0072] wherein X is halo are useful intermediates for the synthesis of anumber of compounds possessing antiviral activity. The compounds offormula I are prepared according to the present invention, by (a)cyclizing 4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole toyield a compound of formula II:

[0073] and (b) reacting the compound of formula 11 with PO(X)₃ toprepare a compound of formula I.

[0074] Each step of the reaction is typically carried out in a solvent.For example, step (a) of the foregoing process may be carried out in anaprotic solvent, such as tetrahydrofuran. Step (b) may be carried out ina solvent such as ethyl acetate. Preferably, step (b) is carried out atreflux.

[0075] In one preferred embodiment, the process comprises the furtherstep (c) of crystallizing the compound of formula I from ethyl acetate.

[0076] According to a preferred embodiment, the present inventionprovides a process for preparing compounds of formula I wherein X is Br.According to another embodiment, compounds of formula I wherein X is Clare synthesized.

[0077] According to one preferred embodiment, the present inventionprovides a process for preparing 2-bromo-5,6-dichlorobenzimidazole whichcomprises reacting a 5,6-dichlorobenzimidazole-2-one with phosphorousoxybromide. Also according to the present invention,5,6-dichlorobenzimidazole-2-one is prepared by cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole.

[0078] The process of the present invention provides a number ofdistinct advantages over conventional processes for preparing2-halo-5,6-dichloro-benzimidazole. The process of the present inventionis more reliable and suitable for the large scale synthesis of2-halo-5,6-dichloro-benzimidazoles than conventional processes. Forexample, a conventional process for the conversion of the5,6-dichloro-benzimidazole-2-one to the2-halo-5,6-dichloro-benzimidazole involves a non-aqueous diazotisationwhich can be capricious and unreliable in large-scale synthesis. Theprocess of the present invention also utilizes milder, less toxic andmore environmentally conscious reagents. Cyanogen bromide isconventionally used for the cyclization of the phenylene diamine; theprocess of the present invention utilizes carbonyl di-imidazole. Theprocess of the present invention provides the further advantage ofimproved yield over conventional processes.

[0079] The compounds of formula I may serve as intermediates in aprocess for synthesizing compounds of formula X:

[0080] wherein:

[0081] R is selected from the group consisting of halo, hydroxy, azido,C₁₋₈alkyl, trihalomethyl, C₁₋₈alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₄arylC₂₋₆alkenyl, C₆₋₁₄arylC₂₋₈alkynyl,

[0082] —NR²⁵R²⁶ wherein R²⁵ and R²⁶ may be the same or different and areeach independently selected from the group consisting of H, halo,C₁₋₈alkyl, cyanoC₁₋₈alkyl, hydroxyC₁₋₈alkyl, haloC₁₋₈alkyl,C₃₋₇cycloalkyl, C₁₋₈alkyl-C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₃₋₇cycloalkylC₁₋₈alkyl, C₂₋₆alkynyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₆alkyl,heterocytlylC₁₋₈alkyl, C₁₋₈alkylcarbonyl, and C₆₋₁₄aryl-sulfonyl or R²⁵and R²⁶ together with the N atom to which they are attached form a 3, 4,5, or 6-membered heterocyclic ring;

[0083] —NHNR³⁰R³¹ wherein R³⁰ and R³¹ are the same or different and areeach independently C₁₋₆alkyl;

[0084] —N═NNC₁₋₆alkyl;

[0085] —NHOC₁₋₆alkyl;

[0086] —OR²⁷ wherein R²⁷ is selected from the group consisting ofC₁₋₈alkyl, C₃₋₇cycloalkyl, and C₆₋₁₄aryl;

[0087] SR²⁸ wherein R is selected from the group consisting of H,C₁₋₈alkyl, hydroxyC₁₋₈alkyl, C₃₋₇cycloalkyl, C₆₋₁₄aryl, andC₆₋₁₄arylC₁₋₆alkyl;

[0088] R¹⁵ is selected from the group consisting of H, halo, C₁₋₆alkylor C₂₋₆alkenyl;

[0089] R¹⁶ and R¹⁷ may be the same or different and are eachindependently selected from the group consisting of H, halo, C₁₋₈alkyl,C₆₋₁₄aryl, heterocyclylC₁₋₈aryl, C₁₋₈alkoxy, haloC₁₋₈alkyl, NO₂, andSR²⁹ where R²⁹ is selected from the group consisting of H, C₁₋₈alkyl,C₆₋₁₄aryl or C₆₋₁₄arylC₁₋₈alkyl; and

[0090] R²⁰ is a D- or L-sugar moiety selected from the group consistingof:

[0091] wherein

[0092] R²¹ and R²² may be the same or different and are eachindependently selected from the group consisting of H, hydroxy,protected hydroxy group, halo, C₁₋₈alkyl, C₁₋₈alkylhydroxy,haloC₁₋₈alkyl, or C₁₋₈alkoxy;

[0093] R²³ is selected from the group consisting of H, hydroxy,protected hydroxy group, C₁₋₈alkyl, C₁₋₈alkoxy, CH₂R³² wherein R³² ishydroxy, protected hydroxy group, halo, or azido; and C(R³³)₃ whereineach R³³ is halo;

[0094] and wherein R²¹, R²² and R²³ may be in the α- or β-position;

[0095] and pharmaceutically acceptable derivatives and prodrugs thereof.

[0096] The process for preparing compounds of formula X proceedsgenerally, according to the following Scheme 1:

[0097] wherein R, R¹⁵, R¹⁶, R¹⁷, R²⁰ and X are as defined above.

[0098] Generally, the process comprises the steps of: (a) cyclizing thephenylenediamine of formula XI with carbonyl di-imidazole to yield acompound of formula XII; (b) reacting the compound of formula XII withPO(X)₃ to prepare a compound of formula XII; and (c) reacting thecompound of formula XIII with a 5- or 6-membered, D- or L-sugar, whichis selected from the group consisting of:

[0099] wherein L is a leaving group in the α- or β-position, for examplea halo, an alkyl- or aryl-thio (such as phenylthio) or an aryl oraliphatic ester group (such as benzoate or acetate). In one embodiment,L is an acetate leaving group.

[0100] The first steps of the process, for the preparation of compoundsof formula XIII, are the same as those described hereinabove for thepreparation of compounds of formula I. Compounds of formula XIII may bereacted with the 5- or 6-membered D- or L-sugars of formulas A-D toprepare the preferred compounds of formula X wherein R is halo.Processes for coupling the substituted benzimidazole base to the sugarare described in PCT Publication Nos. WO 98/56761, WO 92/07867, WO96/01833, WO 97/25337, and WO 99/06424, the subject matter of each isincorporated herein by reference in its entirety.

[0101] Preferred 5- or 6-membered D- or L-sugars for coupling to thebenzimidazole base include the 5-membered D- and L-sugars of formulas Aand B and the six-membered D-sugars of formula D. More preferably, thesugar is a 5-membered L-sugar of formula B or the six-membered D-sugarof formula D.

[0102] The sugars may be in the α- or β-configuration. Preferred sugarsfor coupling to the benzimidazole base include β-L-ribofuranosyls,β-D-ribofuranosyls, 5′-deoxy-β-D-ribofuranosyls, β-D-ribopyranosyls, andα-L-lyxofuranosyls. Particularly preferred sugars includeβ-L-ribofuranosyls and β-D-ribopyranosyls.

[0103] As an alternative to the 5- and 6-membered sugars describedabove, the process of the present invention may also be employed for thesynthesis of carbocyclic substituted benzimidazole derivatives bycoupling the benzimidazole base of formula XIII to a 5- or 6-memberedcarbocyclic moiety instead of the sugar. Suitable carbocyclic moietiesand processes for coupling a benzimidazole base to a carbocyclic moietyare known in the art.

[0104] Optionally, the foregoing process may include one or moreadditional steps. In one preferred embodiment, the process optionallyincludes the additional step of (i) converting the compound of formula Xto a further compound of formula X. For example, the compound of formulaX wherein R is halo may be converted to another compound of formula Xwherein R is other than halo.

[0105] Generally, the process of converting a compound of formula Xwherein R is halo into a further compound of formula X wherein R isother than halo, involves nucleophilic substitution. Methods are knownin the art for the conversion of 2-halo benzimidazoles (e.g., compoundsof formula X wherein R is halo) to 2-substituted benzimidazoles (e.g.,compounds of formula X wherein R is —NR⁸R⁹, etc.) by nucleophilicsubstitution. For example, such methods are described in PCT PublicationNos. WO 98/56761, WO 92/07867, WO 96/01833, WO 97/25337, and WO99/06424, already incorporated herein by reference. Examples of suitablenucleophiles for reaction with the compound of formula X wherein R ishalo include but are not limited to amines, alkoxides, mercaptans,hydrazines, alkylazos, and alkoxyamines. For example, compounds offormula X wherein R is —NR⁸R⁹ may be prepared by reacting compounds offormula X wherein R is halo with an amine nucleophile of formulaH—NR⁸R⁹. Typically the reaction is effected at elevated temperature,70-80° C. in an organic solvent such as ethanol or dimethyl sulfoxide.Suitable amine nucleophiles are commercially available or are readilyprepared by one skilled in the art.

[0106] The process may also optionally include any one or more of thefollowing additional steps, which may be performed in any desired ornecessary order:

[0107] (ii) removing any remaining protecting group(s) on the compoundof formula X (e.g., when any one or more of R²¹, R²², and R²³ is aprotected hydroxy group, e.g., O-acetyl);

[0108] (iii) converting a compound of formula X into a pharmaceuticallyacceptable derivative or prodrug thereof;

[0109] (iv) converting a pharmaceutically acceptable derivative orprodrug of a compound of formula X into a compound of formula X;

[0110] (v) converting a pharmaceutically acceptable derivative orprodrug of a compound of formula X into a further pharmaceuticallyacceptable derivative or prodrug thereof, and

[0111] (vi) separating the alpha and beta anomers of the compound offormula X or a pharmaceutically acceptable derivative or prodrugthereof.

[0112] Methods for carrying out each of the foregoing optional,additional steps are known in the art and are described in PCTPublication Nos. WO 98156761, WO 92/07867, WO 96/01833, WO 97/25337, andWO 99/06424, already incorporated herein by reference.

[0113] The present invention further provides methods for preparingcertain preferred compounds for formula X. Preferred compounds offormula X which can be prepared according to the methods of the presentinvention include but are not limited to compounds of formula VI:

[0114] wherein R is halo; R¹ is hydrogen; and each of R², R³, R⁴, R⁵, R⁶and R⁷ is independently selected from the group consisting of H, hydroxyand protected hydroxy group; and pharmaceutically acceptable derivativesand prodrugs thereof.

[0115] More specifically, preferred compounds which can be preparedaccording to the methods of the present invention include but are notlimit to compounds of formula VI wherein the pyranosyl moiety is a β-Dpyranosyl; compounds of formula VI wherein R², R⁴ and R⁶ are eachhydroxy or O-acetyl; compounds wherein R³, R⁵, and R⁷ are each H, andcompounds wherein R is Br. Particularly preferred compounds of formulaVI include compounds wherein the pyranosyl moiety is a β-D pyranosyl,R², R⁴ and R⁶ are each hydroxy or O-acetyl, R³, R⁵, and R⁷ are each H,and R is Br. According to one preferred embodiment of the presentinvention, 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof isprepared. According to another preferred embodiment,2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-13-D-ribopyranosyl)-1H-benzimidazoleand pharmaceutically acceptable salts and derivatives thereof areprepared.

[0116] Compounds of formula VI can be prepared by a process comprisingthe steps of:

[0117] (a) cyclizing 4,5-dichloro-o-phenylenediamine with carbonyldi-imidazole to yield a compound of formula II:

[0118] (b) reacting the compound of formula II with PO(X)₃ wherein X ishalo, to prepare a compound of formula I:

[0119] (c) reacting the compound of formula I with a pyranoside offormula IV:

[0120] wherein each of R², R³, R⁴, R⁵, R⁶ and R⁷ is independentlyselected from the group consisting of H, hydroxy and protected hydroxygroup (for example O-acetyl). The acetate leaving group (—OAc) is in theα- or β-position. According to one preferred embodiment of the process,X is Br. According to one preferred embodiment, the pyranoside is β-Dpyranoside.

[0121] Steps a) and b) for preparing compounds of formula I aredescribed herein above. Methods for carrying out step c) for couplingthe benzimidazole base of formula I to the pyranoside are described inPCT WO No. 98/56761, the disclosure of which is already incorporated byreference in its entirety.

[0122] As with processes for preparing compounds of formula X, processesfor preparing compounds of formula VI may optionally include one or moreadditional steps, which may be performed in any desired or necessaryorder:

[0123] (i) converting a compound of formula VI into a further compoundof formula VI, such as for example, by the nucleophilic substition atthe 2-postion of a 2-halo-5,6-dichloro-benzimidazole-pyranoside compoundof formula VI;

[0124] (ii) removing any remaining protecting group(s) on the compoundof formula VI (e.g., when any one or more of R¹-R⁷ is a protectedhydroxy group);

[0125] (iii) converting a compound of formula VI into a pharmaceuticallyacceptable derivative or prodrug thereof;

[0126] (iv) converting a pharmaceutically acceptable derivative orprodrug of a compound of formula VI into a compound of formula VI;

[0127] (v) converting a pharmaceutically acceptable derivative orprodrug of a compound of formula VI into a further pharmaceuticallyacceptable derivative or prodrug thereof; and

[0128] (vi) separating the alpha and beta anomers of the compound offormula VI or a pharmaceutically acceptable derivative or prodrugthereof.

[0129] The processes for carrying out these additional, optional stepsare described above with reference to processes for making compounds offormula X.

[0130] The present invention further provides processes for preparingother preferred compounds for formula X. Another preferred class ofcompounds of formula X include but are not limited to compounds offormula V or VII:

[0131] wherein:

[0132] X is halo;

[0133] R is —NR⁸R⁹ where R⁸ and R⁹ are each independently selected fromthe group consisting of H, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl, andCOC₁₋₆alkyl;

[0134] each R¹⁰ is independently selected from the group consisting ofhydroxy and protected hydroxy group;

[0135] and pharmaceutically acceptable derivatives and prodrugs thereof.

[0136] More specifically, preferred compounds which can be preparedaccording to the methods of the present invention include but are notlimit to compounds of formula VII wherein one of R⁸ and R⁹ is H;compounds wherein R⁸ is C₁₋₆alkyl and R⁹ is H; compounds wherein R isisopropylamino; compounds wherein the furanosyl moiety:

[0137] is β-L-ribofuranosyl or β-D-lyxofuranosyl, preferablyβ-L-ribofuranosyl; compounds wherein each R¹⁰ is protected hydroxy,preferably O-acetyl; and compounds wherein each R¹⁰ is hydroxy.Particularly preferred compounds of formula VI include compounds whereinR is isopropylamino, the furanosyl moiety is β-L-ribofuranosyl, and eachR¹⁰ is protected hydroxy, preferably O-acetyl. Other particularlypreferred compounds of formula VII include compounds wherein R isisopropylamino, the furanosyl moiety is β-L-ribofuranosyl, and each R¹⁰is hydroxy.

[0138] According to one preferred embodiment of the present invention,2-bromo-5,6-dichloro-1-β-D-ribofuranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof isprepared. According to another preferred embodiment,2-bromo-5,6-dichloro-1-(2,53,5-tri-O-acetyl-p-D-ribofuranosyl)-1H-benzimidazoleand pharmaceutically acceptable derivatives and prodrugs is prepared.

[0139] The process for preparing compounds of formula V comprises thesteps of: (a) cyclizing 4,5-dichloro-o-phenylenediamine with carbonyldi-imidazole to yield a compound of formula II:

[0140] (b) reacting the compound of formula 11 with PO(X)₃ wherein X ishalo, to prepare a compound of formula I:

[0141] (e) reacting the compound of formula I with a furanosyl offormula III:

[0142] The acetate leaving group (—OAc) is in the α- or β-position.

[0143] The process for preparing compounds of formula VII comprisessteps (a) through (c) above and the further step (d) of reacting thecompound of formula V with an amine of formula H—NR⁸R⁹.

[0144] Steps a) and b) for preparing compounds of formula I aredescribed herein above. Methods for carrying out step c) for couplingthe benzimidazole base of formula I to the pyranoside are described inPCT WO Nos. 96/01833, 92/07867, 97/25337 and 99/06424, the disclosuresof which are already incorporated herein by reference in their entirety.

[0145] As with a processes for preparing compounds of formula V and VIImay optionally include one or more additional steps, which may beperformed in any desired or necessary order:

[0146] (i) removing any remaining protecting group(s) on the compound offormulas V or VII (e.g., when any one or more R¹⁰ is a protected hydroxygroup);

[0147] (ii) converting a compound of formula V or VII into apharmaceutically acceptable derivative or prodrug thereof;

[0148] (iii) converting a pharmaceutically acceptable derivative orprodrug of a compound of formula V or VII into a compound of formula Vor VII;

[0149] (iv) converting a pharmaceutically acceptable derivative orprodrug of a compound of formula V or VII into a furtherpharmaceutically acceptable derivative or prodrug thereof; and

[0150] (v) separating the alpha and beta anomers of the compound offormula V or VII or a pharmaceutically acceptable derivative or prodrugthereof.

[0151] According to one preferred embodiment, the present inventionprovides a process for preparing a compound of formula VII wherein oneor more of R¹⁰ is a protected hydroxy group, and the process furthercomprises the additional step (i) of removing any protecting groups.

[0152] The following examples are intended for illustration only and arenot intended to limit the scope of the invention in any way, theinvention being defined by the claims which follow.

[0153] In the following examples, “g” means grams; “mL” meansmilliliters; “L” means liters; “mmol” means millimoles; “nm” meansnanometers; “h” means hour(s); ““C” means degrees Centigrade; and allpercents (%) are in percent by weight unless otherwise noted.

EXAMPLE 1 5,6-Dichloro-1,3-dihydro-2H-benzimidazol-2-one

[0154] Process A:

[0155] Carbonyl di-imidazole (75 g, 463 mmol) was added, in portionsover 10-15 minutes to a stirred solution of 4,5-dichlorophenylenediamine(72 g, 407 mmol) in tetrahydrofuran (330 mL). The reaction mixture wascooled and stirred at room temperature for 3 h, diluted with water (400mL), cooled to ca 10° C. and the solid was collected by filtration,washed with water and dried, in vacuo, to give the title compound (84 g,414 mmol, 980/% yield) as a white solid.

[0156] Process B:

[0157] A solution of 4,5-dichlorophenylenediamine (10 g, 56 mmol) intetrahydrofuran (35 mL) was added slowly to a stirred suspension ofcarbonyl di-imidazole (9.6 g, 59 mmol) in tetrahydrofuran (10 mL). Theresultant suspension was cooled to room temperature, stirred for 1 hour,diluted with water (60 mL) and cooled to ca 5 deg C. The solid wascollected by filtration, washed with water and dried, in vacuo, to givethe title compound (10.9 g, 54 mmol, 95% yield) as a white solid.

EXAMPLE 2 2-Bromo-5,6-dichloro-1H-benzimidazole

[0158] Phosphorus oxybromide (211 g, 738 mmol) was added slowly to astirred suspension of the compound of Example 1 (50 g, 246 mmol) inethyl acetate (1.25 L). The stirred reaction mixture was heated atreflux for 29 h, cooled to ca 20° C. and then added slowly to water (1L). The organic phase was separated, washed with water (3 L), treatedwith charcoal, and evaporated to give a solid which was slurried in amixture of ethyl acetate:iso-octane (1:1, 200 ml), filtered and dried(50 g, 189 mmol, 77% yield). A portion of the solid (28.5 g) waspurified by dissolving in hot ethyl acetate (1.14 L), the resultantsolution was clarified by filtration, concentrated to ca 140 ml, cooledto ca 5° C. The product was collected by filtration, washed and dried,in vacuo, to give the title compound (22 g) as a white solid.

EXAMPLE 32-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-p-D-ribopyranosyl)-1H-benzimidazole

[0159] 2-Bromo-5,6-dichlorobenzimidazole (4.0 g, 15 mmol),N,O-bis(trimethylsiyl)acetamide (Aldrich, 3.7 mL, 15 mmol), and1,2-dichloroethane (Aldrich Sure Seal were combined and refluxed undernitrogen for 0.5 h. The solution was cooled to room temperature andtrimethylsilyl triflate (Aldrich, 3.2 ml, 16 mmol) was added.Immediately, 4.8 g (15 mmol) solid1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution wasstirred under nitrogen at reflux for 0.5 h, then poured into 7% aqueoussodium bicarbonate and extracted with dichloromethane. The organiclayers was dried with magnesium sulfate (anhyd.), filtered, andevaporated. The crude residue was purified on a silica gel column (5×20cm, 230-400 mesh) with CH₂Cl₂ to give2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazolewhich was fractionated in two parts based on elution. The faster productfraction was impure (1.9 g) and purified by a second column to give 1.4g (2.7 mmol); the slower product fraction was (3.0 g, 5.7 mmol) for atotal yield of 56%; m.p. 100-110° C.; ¹H NMR (DMSO-d₆) δ 8.39 (s, 1H),7.91 (s, 1H), 5.95-5.92 (d, 1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6 Hz),5.67 (bs, 2H), 4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz), 4.00-3.95(overlapping dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).

[0160] Anal. Calcd. for C₁₈H₁₇N₂O₇Cl₂Br: C, 41.25; H, 3.27; N, 5.34.

[0161] Found: C, 41.35; H, 3.28; N, 5.38.

EXAMPLE 4 2-Bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole

[0162] 3.0 g (5.7 mmol)2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazolewas deprotected as using the general procedure summarized in theforegoing description by being dissolved in 60 ml dioxane and theresultant solution cooled in an ice bath between 0 and 5° C. To thissolution was added all at once, 22 ml (22 mmol) of 1 M aq. LiOH. Themixture was removed from the ice bath and allowed to stir at ambienttemperature for 1 h. The mixture was diluted with 120 ml of pH 7phosphate buffer and extracted with ethyl acetate. The ethyl acetatelayer was dried over magnesium sulfate (anhyd.), filtered and solventsevaporated. The residue was triturated in dichloromethane and 1.7 g (4.3mmol, 75% yield) of2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole was collectedby vacuum filtration. The product was dried in a vacuum oven at 50° C.overnight; m.p. 175° C. (decomposes); ¹H NMR (DMSO-d₆) δ 7.96 (s, 1H),7.07 (s, 1H), 5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz),5.13-5.12 (d, 1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06 (m,1H), 3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).

[0163] Anal. Calcd. for C₁₂H₁₁N₂O₄Cl₂Br: C, 36.21; H. 2.79; N. 7.04.

[0164] Found: C, 36.18; H, 2.91; N. 6.88.

EXAMPLE 52-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole

[0165] 2-Bromo-5,6-dichlorobenzimidazole (1.0 g, 3.8 mmol),N,O-bis(trimethylsilyl)acetamide (Aldrich, 0.94 mL, 3.8 mmol), andacetonitrile (Aldrich Sure Seal, 25 mL) were combined and refluxed undernitrogen for 1 h. The solution was cooled to rt and trimethylsilyltriflate (Aldrich, 1.5 mL, 7.6 mmol) was added. After 15 min, solid1,2,3,4-tetra-O-acetyl-L-ribofuranose (1.2 g, 3.8 mmol), prepared by themethod of Guthrie and Smith (Chemistry and INdustry, 1968, pp547-548)except that L-ribose was used as the starting material, was added. Thesolution was stirred under nitrogen at rt for 18 h, then poured into 10%aqueous sodium bicarbonate (100 mL) and extracted with dichloromethan(2×150 mL) The organic layers were dried with magnesium sulfate (anhyd),filtered, and evapoated. The crude residue was purified on a silica gelcolumn (5×20 cm, 230-240 mesh) with 1:30 acetone: CH₂Cl₂ to give thetitle compound (1.2 g, 2.2 mmol, 60%); m.p. 142° C.; [a]²⁰D=(+)87.4(c=0.5 DMF); UVλ_(max) (E) pH=7.0: 298 nm (7,600), 289 (7,400), 254(8,800); 0.1 nNaOH: 298 nm (7,600), 289 (7,400), 256 (7,300); MS (El):m/z (rel. intensity) 524 (0.15, M+); ¹H NMR (DMSO-d₆) d 8.08 (s, 1H,Ar—H), 8.01 (s, 1H, Ar—H), 6.22 (d, 1H, H-1′, J=7.1 Hz), 5.56 (dd, ₁H,H-2′, J=7.1 Hz, J=7.2 Hz), 5.45 (dd, 1H. H-3′, J-7.2 Hz, J=4.5 Hz),4.55-4.47 (m, 2H, H-4′ and 5′), 4.37 (d, 1H, H-5”, J=9.7 Hz), 2.15 (s,3H, OAc), 2.14 (s, 3H, OAc), 2.01 (s, 3H, OAc).

[0166] Anal. Calcd. for C₁₈H₁₇N₂O₇Cl₂Br: C, 41.25; H, 3.27; N, 5.34.

[0167] Found: C, 41.16; H, 3.39; N, 5.20.

[0168] In addition, a small amount of the alpha anomer(2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-alpha-L-ribofuranosyl)-1H-benzimidazole)was obtained (0.11 g, 0.22 mmol, 6%); m.p. <65° C.; [a]²⁰D=(−)206.8(c=0.5 DMF); MS (AP+): m/z (rel. intensity): 524 (0.8, M+); ¹H NMR(DMSO-d₆) d 7.95 (s, 1H, Ar—H), 7.91 (s, 1H, Ar—H), 6.66 (d, 1H, H-1′,J=4.2 Hz), 5.68 (t, 1H. H-2′, J=4.6 Hz), 5.52 (t, 1H. H-3′, J=5.9 Hz),4.87-4.81 (m, 1H, H-4′), 4.37-4.24 (m, 2H, H-5′), 2.08 (s, 3H, OAc),2.03 (s, 3H, OAc), 1.51 (s, 3H, OAc).

[0169] Anal. Calcd. for C₁₈H₁₇N₂O₇Cl₂Br: C, 41.25; H, 3.27; N, 5.34.

[0170] Found: C, 41.39; H, 3.35; N, 5.29.

EXAMPLE 6 2-Bromo-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole

[0171] Sodium carbonate (0.28 g, 2.65 mmol) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole(1.39 g, 2.65 mmol) were combined with water (4 mL), methanol (20 mL)and ethanol (20 mL) and stirred at rt for 1.5 h. Acetic acid (0.3 mL,5.3 mmol) was added and the suspension was concentrated to a solid.Purification of the residue on a silica gel column (2.5×20 cm, 230-400mesh) with 1:9 ethanol:CH₂Cl₂ gave the title compound as a whiteamorphous solid (0.79 g, 2.0 mmol, 75%); m.p. 169° C.; [a]²⁰D=(+)105(c=0.5 DMF); UVλ_(max) (E) pH=7.0: 298 nm (6,700), 289 (6,500), 255(6,900); 0.1 nNaOH: 298 nm (6,700), 295 (5,400), 256 (6,700); MS (Cl):m/z 399 (M+); ¹H NMR (DMSO-d₆) d 8.57 (s, 1H, Ar—H), 7.96 (s, 1H, Ar—H),5.89 (d, J=7.9 Hz, H-1′), 5.48 (d, ₁H, OH, J=6.3 Hz), 5.42 (t, ₁H, OH,J=4.5 Hz), 5.29 (d, 1H, OH, J=4.2 Hz), 4.43 (apparent dd, 1H, H-2′,J=13.3 Hz, J=6.1 Hz), 4.14 (apparent t, 1H, H-3′, J=4.3 Hz), 4.01(apparent d, 1H, H-4′, J=1.7 Hz), 3.77-3.63 (m, 2H, H-5′).

[0172] Anal. Calcd. for C₁₂H₁₁N₂O₄Cl₂Br.0.20C₂H₆O: C, 36.57; H, 3.02; N,6.88.

[0173] Found: C, 36.68; H, 2.85; N, 7.05.

EXAMPLE 75,6-Dichloro-2-(isoproylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole

[0174] soprylamino (10 mL) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole(1.0 g, 1.9 mmol) were combined with absolute ethanol (20 mL) andstirred at 75° C. for 48 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 vm×16 cm, 230-400 mesh) with 1:20methanol: dichloromethane to give product contaminated with a smallamount of higher R_(f) material. This was repurified on a chromatotron,fitted with a 2 mm silica gel rotor, with 1:25 methanol:dichloromethaneto give a white solid (0.43 g, 1.15 mmol, 60%); [a]²⁰D=(−)22.4 (c=0.5DMF); UVλ_(max) (E): pH 7.0:304 nm (95,00), 275 (1,800) 260 (8,300); 0.1NaOH: 304 nm (9,900), 275 (19,00), 260 (8,100); MS (Cl): m/z (rel.intensity) 376 (100, M+1); ¹H NMR (DMSO-d₆) d 7.59 (s, 1H, Ar—H), 7.35(s, 1H, Ar—H), 6.90 (d, ₁H. NH, J=7.8 Hz), 5.73 (d, 1H. H-1′, J=6.5 Hz),5.62 (t, 1H, OH, J=4.2 Hz), 5.27-5.23 (m, 2H, OH), 4.27 (apparent dd,1H, J=13.4 Hz, J=7.6 Hz), 4.11-3.99 (m, 2H), 3.97 (br. s, 1H), 3.72-3.61(m, 2H, H-5′), 1.18 (d, 6H, CH(CH₃)2, J=6.6 Hz).

[0175] Anal. Calcd. for C₁₅H₁₉N₃O₄Cl₂.1.00H₂O: C, 45.70; H, 5.37; N,10.66.

[0176] Found: C, 45.75; H, 4.98; N, 10.50.

EXAMPLE 105,6-Dichloro-2-(cyclopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole

[0177] Cyclopentylamine (5 mL) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 70° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 vm×16 cm, 230-400 mesh) with 1:9ethanol: dichloromethane to give a white solid (0.27 g, 0.68 mmol, 59%);m.p. 140° C.; [a]²⁰D=(−) 24.0 (c=0.5 DMF); UVλ_(max) (E): pH 7.0: 305 nm(12,700), 276 (2,400) 260 (10,600), 245 (7400); 0.1 N NaOH: 305 nm(12,600), 276 (2,200), 260 (9,900), 247 (7,300); MS (Cl): m/z (rel.intensity) 402 (100, M+1); ¹H NMR (DMSO-d₆) d 7.60 (s, 1H, Ar—H), 7.36(s, 1H, Ar—H), 6.91 (d, 1H, NH, J=6.8 Hz), 5.74 (d, 1H, H-1′, J=7.6 Hz),5.61 (t, 1H, OH, J=4.2 Hz), 5.26 (d, 1H, OH, J=8.1 Hz), 5.23 (d, 1H, OH,J=5.5 Hz), 4.30-4.14 (m, 2H, NHCH, H-2′), 4.05 (apparent t, 1H, H-3′,J=4.9 Hz), 3.96 (br. s, 1H. H-4′), 3.72-3.59 (m, 2H, H-5′), 1.91 (br. s,2H, CH₂), 1.66 (br. s, 2H, CH₂), 1.52 (br. s, 4H, CH₂).

[0178] Anal. Calcd. for C₁₇H₂₁N₃O₄Cl₂.0.20H₂O: C, 50.31; H, 5.31; N,10.38.

[0179] Found: C, 50.13; H, 5.31; N, 10.05.

1. A process for preparing a compound of formula I:

wherein X is halo, said process comprising the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

and (b) reacting the compound of formula 11 with PO(X)₃ to prepare acompound of formula
 1. 2. The process according to claim 1, wherein X isBr.
 3. A process for preparing 2-bromo-5,6-dichlorobenzimidazole, saidprocess comprising reacting a 5,6-dichlorobenzimidazole-2-one withphosphorous oxybromide.
 4. A process for preparing a compound of formulaVI:

wherein: R is halo; R¹ is hydrogen; and each of R², R³, R⁴, R⁵, R⁶ andR⁷ is independently selected from the group consisting of H, hydroxy andprotected hydroxy group; and pharmaceutically acceptable derivatives andprodrugs thereof; said process comprising the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole to yield acompound of formula II:

(b) reacting the compound of formula II with PO(X)₃ wherein X is halo,to prepare a compound of formula I:

(c) reacting the compound of formula I with a pyranoside of formula IV:

to prepare a compound of formula VI and pharmaceutically acceptablederivatives and prodrugs thereof.
 5. The process according to claim 4,wherein said pyranoside of formula IV is a beta-D pyranoside; R², R⁴,and R⁶ are each hydroxy or O-acetyl; R³, R⁵, and R⁷ are each H; and Xand R are Br.
 6. A process for preparing2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs ref, said processcomprising: (a) reacting 5,6-dichlorobenzimidazol-2-one with phosphorousoxybromide to produce 2-bromo-5,6-dichlorobenzimidazole; (b) reacting2-bromo-5,6-dichlorobenzimidazole with1,2,3,4-tetra-O-acetyl-β-D-ribopyranose to produce2-bromo-5,6-dichloro-11-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazole;and (c) deprotecting2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl)-β-D-ribopyranosyl)-1H-benzimidazoleto produce 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole andpharmaceutically acceptable derivatives and prodrugs thereof.
 7. Theprocess according to claim 6, further comprising the step of preparing5,6-dichlorobenzimidazol-2-one by cyclizing4,5-dichloro-o-phenylenediamine with carbonyl di-imidazole.
 8. A processfor preparing compounds of formula VII:

wherein: R is —NR⁸R⁹ where R⁸ and R⁹ are each independently selectedfrom the group consisting of H, C₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl, and COC₁₋₆alkyl; and each R¹⁰ isindependently selected from the group consisting of hydroxy andprotected hydroxy group; and pharmaceutically acceptable derivatives andprodrugs thereof; said process comprising the steps of: (a) cyclizing4,5-dichloro-o-phenylenediamine with carbonyl d i-imidazole to yield acompound of formula II:

(b) reacting the compound of formula II with PO(X)₃ wherein X is halo,to prepare a compound of formula I:

(c) reacting the compound of formula I with a furanosyl of formula III:

to prepare a compound of formula V:

(d) reacting the compound of formula V with an amine of formula H—NR⁸R⁹;to prepare a compound of formula VII and pharmaceutically acceptablederivatives and prodrugs thereof.
 9. The process according to claim 8,wherein one or more of R¹⁰ is protected hydroxy group and said processfurther comprises the step of removing any protecting groups.
 10. Theprocess according to claim 8, wherein R is isopropylamino and thefuranosyl moiety:

is β-L-ribofuranosyl.
 11. A process for preparing compounds of formulaX:

wherein: R is selected from the group consisting of halo, hydroxy,azido, C₁₋₈alkyl, trihalomethyl, C₁₋₈alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₄arylC₂₋₆alkenyl, C₆₋₁₄arylC₂₋₆alkynyl, —NR²⁵R²⁶ wherein R²⁵ and R²⁶may be the same or different and are each independently selected fromthe group consisting of H, halo, C₁₋₈alkyl, cyanoC₁₋₈alkyl,hydroxyC₁₋₈alkyl, haloC₁₋₈alkyl, C₃₋₇cycloalkyl,C₁₋₈alkylC₃₋₇cycloalkyl, C₂₋₆alkenyl, C₃₋₇cycloalkylC₁₋₈alkyl,C₂₋₆alkynyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₆alkyl, heterocyclylC₁₋₈alkyl,C₁₋₈alkylcarbonyl, and C₆₋₁₄arylsulfonyl; —NHNR³⁰R³¹ wherein R³⁰ and R³¹are the same or different and are each independently C₁₋₆alkyl;—N═NNC₁₋₆alkyl; —NHOC₁₋₆alkyl; —OR²⁷ wherein R²⁷ is selected from thegroup consisting of C₁₋₈alkyl, C₃₋₇cycloalkyl, and C₆₋₁₄aryl; —SR²⁸wherein R²⁸ is selected from the group consisting of H, C₁₋₈alkyl,hydroxyC₁₋₈alkyl, C₃₋cycloalkyl, C₆₋₁₄aryl, and C₆₋₁₄arylC₁₋₆alkyl; R¹⁵is selected from the group consisting of H, halo, C₁₋₆alkyl orC₂₋₆alkenyl; R¹⁶ and R¹⁷ may be the same or different and are eachindependently selected from the group consisting of H, halo, C₁₋₈alkyl,C₆₋₁₄aryl, heterocyclyl-C₁₋₈aryl, C₁₋₈alkoxy, haloC₁₋₈alkyl, NO₂, andSR²⁹ where R²⁹ is selected from the group consisting of H, C₁₋₈alkyl,C₆₋₁₄aryl or C₆₋₁₄arylC₁₋₈alkyl; and R²⁰ is a D- or L-sugar moietyselected from the group consisting of:

wherein R²¹ and R²² may be the same or different and are eachindependently selected from the group consisting of H, hydroxy,protected hydroxy group, halo, C₁₋₈alkyl, C₁₋₈alkylhydroxy,haloC₁₋₈alkyl, or C₁₋₈alkoxy; and R²³ is selected from the groupconsisting of H, hydroxy, protected hydroxy group, C₁₋₈alkyl,C₁₋₈alkoxy, CH₂R³² wherein R³² is hydroxy, protected hydroxy group,halo, or azido; and C(R³³)₃. wherein each R³³ is halo; and wherein R²¹,R²² and R²³ may be in the α- or β-position; and pharmaceuticallyacceptable derivatives and prodrugs thereof; said process comprising thesteps of: (a) cyclizing a phenylenediamine of formula XI:

with carbonyl-di-imidazole yield a compound of formula XII:

(b) reacting the compound of formula XII with PO(X)₃, wherein X is halo,to prepare a compound of formula XIII:

(c) reacting the compound of formula XIII with a 5- or 6-membered, D- orL-sugar selected from the group consisting of:

wherein L is a leaving group in the α- or β-position to preparecompounds of formula X:

wherein R¹⁵, R¹⁶, R¹⁷, and R²⁰ are as defined above and R is halo, andpharmaceutically acceptable derivatives and prodrugs thereof; and (d)optionally converting the compound of formula X or pharmaceuticallyacceptable derivative or prodrug thereof into a further compound offormula X or pharmaceutically acceptable derivative or prodrug thereofby nucleophilic substitution.